AU609359B2 - New indolylpropanols, processes for their preparation and their use, and preparations containing the compounds - Google Patents

Abstract

Substituted indolylpropanols of the formula I <IMAGE> (I) in which R1 denotes a cyano, carboxamido, alkoxycarbonyl, hydroxyl or acetyl group, Y stands for the group A <IMAGE> (A) wherein n is the number 2 or 3, or the group B, <IMAGE> (B) R2 stands for R2' where Y denotes the group A and for R2'' when Y denotes the group B, where R2' denotes pyridinyl, thienyl or substituted phenyl which is monosubstituted or disubstituted by difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, trifluoroethoxy, alkoxyalkoxy, cycloalkylalkoxy, alkoxyalkyl, alkylthioalkoxy, alkylsulphinylalkoxy, alkylsulphonylalkoxy, alkoxyalkylthio, alkoxyalkylsulphinyl, alkoxyalkylsulphonyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl and dialkylaminoalkoxy, and R2'' denotes pyridinyl, thienyl, phenyl or substituted phenyl which is monosubstituted or disubstituted by halogen, alkyl, cycloalkyl, alkoxy, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, trifluoroethoxy, alkoxyalkoxy, cycloalkylalkoxy, alkoxyalkyl, alkylthioalkoxy, alkylsulphinylalkoxy, alkylsulphonylalkoxy, alkoxyalkylthio, alkoxyalkylsulphinyl, alkoxyalkylsulphonyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl and dialkylaminoalkoxy, and R3 stands for R3' when Y denotes the group A and for R3'' when R denotes the group B, where R3' denotes hydrogen, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, trifluoroethoxy, alkoxylalkoxy, alkoxyalkyl, alkylthioalkoxy, alkylsulphinylalkoxy, alkylsulphonylalkoxy, alkoxyalkylthio, alkoxyalkylsulphinyl, alkoxyalkylsulphonyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl or dialkylaminoalkoxy, and R3'' denotes hydrogen, alkoxy, halogen, difluoromethoxy, difluoromethylthio, trifluoromethoxy, trifluoromethylthio, trifluoroethoxy, alkoxyalkoxy, alkoxyalkyl, alkylthioalkoxy, alkylsulphinylalkoxy, alkylsulphonylalkoxy, alkoxyalkylthio, alkoxyalkylsulphinyl, alkoxyalkylsulphonyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl or dialkylaminoalkoxy, or a physiologically tolerable hydrolysable derivative thereof, in which the hydroxyl group in the 2-position of the 3-aminopropoxy side chain is present in esterified form, and also their tautomeric forms and their salts and also acid addition salts, where in all cases previously mentioned alkyl of the alkyl groups or of alkyl moieties or alkylene moieties of groups in each case denotes straight-chain or branched alkyl or alkylene having 1 to 6 carbon atoms and cycloalkyl has 3 to 7 carbon atoms, with the proviso that if R2' denotes pyridinyl or thienyl, R3' does not denote hydrogen, but one of the other R3 radicals mentioned show positive inotropic, vasodilatory and antiarrhythmic action and are suitable for the treatment of cardiac insufficiency, cardiac arrhythmias and hypertonia, coronary heart disease and peripheral and central arterial circulatory disturbances.

Description

COMMONWEALTH OF AUSTR9339 FORM PATENTS ACT 1952 CO0M P LET E S P ECI F IC A FOR OFFICE USE: Class Int.Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: 0 Related Art: t This docuiment coritains the anidnmnts made ilnder Section 09 and is correct for I I Name of Pplicant: BEIERSDORF AKTIENGESELLSCHAFT *t '"Address of Applicant: ';Actual Inventor: Unnastrasse 48, D-2000, Hamburg 20, West Germainy Wolfgang Sten; el, Ben Armah, and Thomas Beuttler -Address fov' Service: SHELSTON WATERS, 55 Clarance S ,reet, Sydney t "Complete Sp(4cification for the Inv;ention entitled: "NEW INDOLYLPROPANOLS, PROCESSES FOR THEIR PREPARATION AND THEIR USE, AND PREPARATIONS CONTAINING THE COMPOUNDS" The following statement a full descriptirmn of this invention, ivcluding the best meth~od of performing it known to us:- 1- 4a- NEW INDLYLROPANOT.S, PFl; =SES FOR THEIR PRPARATION AND THEIR~ USE, AI>D PREP~AAIONS CONTAINING THE COMPOUNDS.

DESMI'ION

The invention relates to new substituted indoLyLpropanoLs of the formula 1 a CH~ iCH 2 Y -CH (1) in wh ichH R Rl denotes a cyano, carboxamido, alkoxycarbony,. hydr'oxyL or acetyL group, Y stands for ihe group A -N M- I (CH 2 )n wherein n is the number 2 or 3, or the group 6,

H

-0 Rstands for R when Y denotev the group A and for R' 1' when Y denotes the group 8, where R 2'denotes pyridinyL, thienyL or substituted 'phenyl which is monosbstituted or dlisubstituted by dlifLuoromethoxy, difLuoromethyLthio, tr ifLuoromethoxy, trifLuorgrmethyLth jo, tr ifLuoroethoxy, aLkoxyalkoxy, cycLoaLkyLaLkoxy, aLkoxyaLkyL, aLkyLthioaLkoxy, aLkyLsuLphinyLatlkoxy, aLkyLsuLphonI.aLkoxy, alkoxyaLkyL thio, aLkoxyaLkyLsuLph inyL, aLkoxyaLkLsulphonyL, aLkyhl 'iaLkYL, aLkyLsuLphinyLaLkyL, aLkyLsuLphonyLaLky4 and d 'atkyLaminoalkoxy, and R denotes pyridinyt, thienyL, phenyL or substituted phenyl which is monosubstituted or disubstitutbd by halogen, aLkyL, cycLoalkyL, aLkoxy, dlifLuoromethaxy, difLu~iromethyL thio, trifLuoromethoxy, trifLuorornethythio, t rif Luo roe thoxy aIkoxya~koxy, cycLoa~kyLaLkoxy, aLkoxya Lky L, a Lkylth i aa Lkoxy, a LkyL suLph i ny La Lkoxy, a Cky LsuL phony La Lkoxy, a L ko xyaLk yL th i a, aL koaxy a LkyL suiph i nyl, a LkoxyaLkyLsuLphonyL, a Lky L th ioa Lky L, aIky Lsuiph inyL a LkyL, aL kyLsuLphonyL aLkyL and d iaLkylam i roaLkox.,, and Rstands for R 3 when Y clenotes the group A and for R 3 when Y 'denotes the group 8, where R 1denotes hydrogen, dif Luoromethoxy, dif LuoromethyL th io, tr if Luoromethoxy, tr if LuoromethyL th io, tr if Luoroetlhoxy, aLkoxydLkoxy, aLkoxyalkyl, aLkyLthioaLkoxy, aLkyLsuLphinyL a Lkoxy, alkyL sti:ph any La Lkoxy, a Lkoxy aLkyithia, aLkoxyaLkyLsuLphinyL, 'LkoxyaLkyLsuLphonyL, aLkyLth loaLkyL, aLkyLsuiph inyl a lkyL alkyL suLphonyL aLkyL or diaLky L aminoa Lkoxy, and R31denotes hydrogen, aLkoxy, halogen, d if Luorome thoxy, difLuoromethyL th ic, trifLuoromethoxy, t rif Luorome thy L:th io, tr if Luoroe thoxy, a Lkoxy a Lkoxy, a LkoxyaLkyL,, a LkyL'th joaLkoxy, aL 'kyLsuLphinyLaLkoxy, aLkyLsuiphonyLaLkoxy, aLkoxya~kyLthio, aLkoxyaLkyLsuLph inyL, aLkoxyaLkyLsuLphonyl L'.akyt th ioa L .y L a L ky Lsu Lp h in y LaLkyL, aLkyL s uLphonyLaLkyl or diaLkyLaminoaLkoxy, or l physiologically tolerable hydroLysabLe derivative thereof, in which the 'hydroxyL group in the 2-pos it i.o n of the 3-am Inopropoxy side chain is present in esteri fied form, au:d also their tautomeric forms~ and their saL-ts and aLso attid addition saLts, where in aLL cases previously mentioncd aLkyL of the aLkyL groups or of aLkyL moieties, or aLkyLene moieties of groups in each case denotes straight-chain or branched aLky, or aLkyLene having 1 to 6 carbons atoms and cycLoaLkyL has 3 to 7 carbcr atoms, with the proviso that if R 1denotes pyridinyl or thierivL-

R

3 does not denote hydrogen, but one of the otherR radicaLs mentioned, and also processes for their preparation ind their use and preparations which contain these compounds.

Physiologically hydroLysabLe derivatives are derivatives which are cleaved under physiological condi tioan s to form~ the corresponding compounds which have a hydroxyL IZ2

I

I~

3 group in the 2-position of the propoxy side chain.

A group of such derivatives in esterified form of the compounds of the formula I consists e.g. of the compounds of the formula la OCOR R 0 CH CH CH 2 Y CH 3 la) H whierein 2 2hvte wherein R R and Y have the abovementioned meaning, S. and *r 4 R stands fo- alkyL having 1 to 12 carbon atoms, cycloalkyL having 3 to 7 carbon atoms, phenyL, phenylalkyl 10 having 7 to 12 carbon atoms, phenyl or phenylalkyl having 7 to 12 carbon atoms which are moncsubstituted in the phenyl ring by alkyL having 1 to 4 carbon atoms, phenyl or phenyLalkyi having 7 to 12 carbon atoms which are monosubstituted or disubstituted in the phenyl ring by S0* S. 15 identicaL or different halogen having an atomic number from 9 to 35, or phenyl or phenylaLkyl having 7 to 12 carbon atoms which are monosubstituted, disubstituted or trisubstituted in the phenyl ring by identical or different alkoxy having 1 to 4 carbon atoms.

20 The compounds of the formula I are preferred in which the hycdroxyl group in the 2-position of the propoxy "o side chain is present in unesterified form.

If R 2 represents pyridinyL or thienyl, Y stands for A and R1 and aLso n have the meaning indicated, R does not denote hydrogen, but one of the other R radicals mentioned. Compounds of the formula I in which Y denotes the group A and in which R 3 denotes hydrogen and R at the same time denotes pyridinyl or thienyl are thereby excluded.

Particularly preferred are the compounds of the for'mulae I or la, in which Y denotes the group B.

For the sake of simplicity, the compounds according to the invention are defined in only one tautomeric form represented by formuLa I. However, the invention t -4applies to all tautomeric forms of the compounds. In particular, the oxindole form of the indole group substituted in the 2-position by hydroxyl is incLuded.

Although pharmaceutically tolerable salts and acid addition salts of the new compounds of the formulae I and la and their tautomeric forms are preferred, all salts are within the range of the invention. ALL salts are valuable for the preparation of the compounds, even when the specific salt is only desired as an intermediate, such as, for example, when the salt is only formed for the purposes of purification or identification or when it is used as an intermediate in the preparation of a pharmaceutically tolerable salt, for example by ion exchange procedures.

The compounds of the general formula I and their salts contain asymmetrical carbon atoms. The invention therefore also relates to the various optical isomers and diastereomers as well as the salts and addition salts' of these compounds with acids. The racemates can be separated into their optical antipodes by methods which are known per se.

Preferred compounds are those in which the' asymmetrical carbon atom C possesses the-S configuration in the propanolamine moiety of the formula I.

Compounds which are structurally related to the compounds of the present invention are described in European Patent Specification No. 25,111' and German Offenlegungsschrift 3,524,955. The compounds of the present invention are, however, neither specifically disclosed nor suggested by these disclosures.

Unless indicated otherwise, the alkyl groups and alkyl moieties or alkylene moieties of groups according to the invention can be straight-chain or branched and they each possess 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 2 carbon atoms.

Examples of such one or more alkyl or alkylene-containing qgoupi are alkoxy, alkoxyalkoxy, alkoxyalkyl, alkylthioalkoxy, alkoxyalkylthio or dialkylalkoxy. Preferred alkyl S or alkene moieties are methyl, ethyl, n-propyl, isopropyl, rsl i I i I~ II butyl or correspondingly methylene, ethylene, n- or isopropylene and butylene.

Cycloalkylalkoxy groups according to the inven- 2 2' 2" tion, e.g. R R 2 and R possess 4 to 13 carbon atoms, in particular 4 to 9 carbon atoms.

The alkoxy radicals of the cycloalkylalkoxy groups have 1 to 6 carbon atoms, methylene, ethyLene and propylene being preferred as alkylene radicas of the alkoxy radicaIs.

Cycloalkyl groups according to the invention, e.g.

R 2, and cycloalkyl moieties such as cycloa.kyl radicals of cyclo-alkylalkoxy groups possess 3 to 7 carbon atoms, in particular 3 to 6 carbon atoms. Cyclopropyl and cyclohexyl are particularly preferred.

St It-I I t 2" 3" 15 Halogen radicals R and R are preferably F, S.t CL, Br, in particular F or CL. Alkyl or alkyl moieties of the alkoxy group of the substituents R 2 and R3" are Cl-6-alkyl, preferably methyl, ethyl, n- and isoprapyl and butyl.

20 Preferred R radicals are hydrogen, alkoxy and *halogen, in particular, however, hydrogen.

Preferred alkoxy groups of the alkoxycarbonyl *1 group R possess 1 to 6, preferably 1 to 4, carbon atoms.

Particularly preferred are methoxy and ethoxy groups.

Preferably R 1 is cyano.

2 2' 2" r Trifluoroethoxy radicals of R R and R or 3 R are preferably F 3

CCH

2 0- radicals.

Pyridinyl is preferably pyridin-4-yl and thienyl is preferably thien-3-yl.

Preferably, R2 is phenyt sr substituted phenyl, in particular, however, phenyl, when Y is the group B.

The phenyL group can carry one or two of the substituents mentioned, which can be identical or different. If the phenyl groups are disubstituted, then the substituents are preferably identical.

2 20 2" Substituted phenyl groups R 2 R and R are preferably substituted in the 3- and/or 4-position with the indicated substituents, in particuLar monosubstituted in the 4-position. Simiary, the radical R3 is preferably -6situated in the 3- or 4-pos it ion, in particular in the 4position.

Prefer-ably, R3is hydrogen. ParticuLarLy prefer-red compounds of the formula I or Ia are those in which Y denotes the group B and R3denotes hydrogen and the other radicals have the indicated meaning, in particu- Lar, however, Rand R are then phenyl.

ALkoxyalkoxy, alkoxyaLkyL, aLkyLthioaLkoxy, aLkytsuLph inyLaLkoxy, aLkyLsuLphonyLaLkoxy, aLkoxyaLkyLthio, aL k o xya Lk y Ls u Lph i ny L a Lko x ya Lky Ls uLp h on y L, a Lky L th io a Lk y L, aLkyLsuLphinyLaLkyL, aLkyLsuLphonyLaLkyL or dia Lk y La m inoa Lk o xy su bs tit u, e n ts R 3 or those substituents of the phenyL group of the radical R 2 prefer-ably p~issess 2-6, i n .pa r i-cuLar 2-4 or 3-6 or 3-4 or also 2 carbon a to ms. Preferred aLkyL or aLkylene m.oQieties in these ra d ica Ls are methyl, ethyl, n-pr-opyL, isopropyL or correspondingLy methyLene, ethyLene and propylene. They ar~e prefer-abLy subst-ituted terminal ly., Particularly preferred radicals of this. type are aLkoxyethoxy, aLkoxymethyL, alkyLthioethoxy,* aLkyLsuLphinyLethoxy, aLkyLsuLphonyLethoxy, aLkox-yethyLth io, aLkoxyethyLsuLphinyL, aLkoxyethyLsu IphanyL aLkyL th iomethyL aLkyLsuL'phinyLmethyL, a Lky Ls u LphonyLmethyL and 2--dimethyLaminoethoxy.

Par'ticuLarLy preferred R 3 rad icals and substituents of the phenyL nucleus of R 2 R 2 and R 2 1 are difluoromethoxy and aLkoxyaLko:xy, prefer-ably aLkoxyethoxy,, in particuL ar methoxyethoxy and aLkoxyaLkyL, prefer-ably aLkoxyme thyL, in particular methoxymethyL. 2-Methoxyethoxy is particularly preferred.

The following compounds of the formula I, their salts and physiologically hydroLysabLe derivatives are preferred: a) (4-difLuoromethoxyphenyL )phenyLmethyL) piper-az in-1-yL)-2-hydroxypropoxy)-1H-indoLe-2-carbon it r iLe b) 4-(3-(4-Cb is-4,4'-difLuoromethoxy-dipheny4methyL)piper-az in-1-yL)-2-hydroxypropoxy)-1H-indoLe-2-carbo- VALIA c) 4-(3-(4-((4-difLuoromethoxyphenyL) (4-pyridinyL)methyL) -7pipera z in--.1-y L -2-hydroxypropoxy) -1H- indo e--ca rbon i t r i L e F 4-d if Luorome thoxyph enyL)(3- th ieny L)me thy L) piper a zin-1 -yL )-2-h-droxypropoxy) -1H-indoLe-2-c arbon itr iL e e) (4-difLuoromethoxyphenyL)phenyLmethyL)piperazin-1-yL)-2-hydroxypropoxy)-lH-jndoLe-2C3H)-one f 4- 2-me thoxye thoxy )-ph eny L )ph eny Lme thy L piperazin-1-yL)-2-hydroxypropoxy)-lH-indoLe-2-carbon itr itLe g) (4-methoxymethyLphenyL )phenyLmethyL)-piperazin-1-yL)-2-hydroxypropoxy)-lH-indoLe-2-carbonitriLe h) 1-diphenyLmethyL-azetidin-3-oxy)-2-hydroxypropoxy)-1H-indoLe-2-carbonitrile The compounds f) and preferably h) are particuLarly preferred, in particular with the S conf igurat i on n the C in the propanoLamine moiety.

The compounds of the formula I1 according to the invention, the ir physiologically tolerable saLts and acid addition sal ts and also their physiologically hydroLysabLe derivatives are therapeutic active compounds, possess a high pharmacological action and are valuabLe *m e d icam en t s. in particular, they show positive- inotropic, vasodilatory and an,-1arrhythmic action and are suitable for the treatment of .ardiac insufficiency, cardiac arrhythmias and hypertonia, coronary heart diseases and peri pheral and centra' arterial circulatory disturbances.

The compounds of the present invention can be used in humans orally or parenteraLLy in a dosage of 1-800 mg, preferably 10-P00 mg, particularly preferably 20-100 mg per day, in partic-iar in subdivided doses, for example three times daily. These dosages are advantageous for the treatment of the previously mentioned diseases, in particular cardiac insufficiency and/or hypertonia and arrhythmias.

The positive inotropic action of the compounds according to the invention was determined on guinea-pig papiLLary muscle (Naunyn-Schmiedeberg's Arch. PharmacoL.

AL1 304, 37, 1978). The concentration of the substance in wU

U.

8 the organ bath was 10 4 mol/l in each case. The maximum percentage increase of the contraction amplitude was determined on three papillary muscles in each case and was at least Accordingly to the invention, pharmaceutical compositions are provided which contain a compound of the formula I or the derivatives hydrolysable under physiological conditions to give the compounds according to the invention, such as e.g. esters or their pharmaceutically tolerable salts, together with a pharmaceutically tolerable diluent or excipient.

The compounds according to the invention can be mixed with the customary pharmaceutically tolerable diluents or excipients and if appropriate with other auxiliaries and, for example, can be administered orally or parenterally. They can be administered orally in the. form of tablets, dragees, syrups, suspensions and liquids or parenterally in the form of solutions or suspensions.

Preparations to be administered orally can contain one or more additives such as sweeteners, aromatizers, colorants and oreservatives. Tablets may contain the active compound mixed with customary pharmaceutically tolerable auxiliaries, for 'example inert di'luents such as calcium carbonate, sodium carbonate, lactose and talc, granulating agents and agents which promote the disintegration of the tablets on oral administration such as starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate, stearic acid and talc.

Suitable excipients are, for example, lactose, gelatin, maize starch, stearic acid, ethanol, propylene glycol, ethers of tetrahydrofurfuryl alcohol and water.

The tablets may be coated by known procedures in order to delay disintegration and absorption in the gastrointestinaL tract, by means of which the activity of the active compound can be extended over a longer time span. Likewise, in suspensions the active compound may be mixed with auxiliaries which are customary for the preparation of such compositions, for example suspending agents such as methylcellulose, tragacanth or sodium 4

L

9 alginate, wettin agents such as lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate and preservatives such as ethyl parahydroxybenzoate. Capsules may contain the active compound as the only component or mixed with a solid diluent such as ':alcium carbonate, calcium phosphate or kaolin. The irjectable preparations are likewise formulated in a manner known per se. The pharmaceutical preparations may contain the active compound in an amount from 0.1 to 90%, in particular 1 to 90%, the residue being an excipient or additive. With respect to preparation and administration, solid preparations such as tablets and capsules are preferred. Preferably, the preparations contain the active compound in an amount from 5-50 mg.

15 The new compounds of the general formula I in S1 2 3 o-o which Y denotes the group A and R R R and n have the meaning indicated can be prepared by reaction of the known compounds of the formula II 0 OCH CH CH 2 l (In H R in which R denotes a cyano, carboxamido, alkoxycarbonyl, oia hydroxyl or acetyl group, I with piperazine derivatives of the formula III

(CH

2 )n /R 2 HN N CH (IIl) in which R 2

R

3 and n have the meaning indicated. The compounds of the formula III can be prepa'cd by known protesses or in analogy to known processes.

The reaction of the compounds of the formula II with the compounds of the formula III is preferably carried out in an alcohol such as ethanol or propanol or in a suitable ether such as dioxane or without solvent Si 10 in the melt of the components. Suitable temperatures are between 20 0 C,to 200 0 C. the reaction being expediently carried out at the reflux temperature of the reaction mixture, if a solvent is present.

The compounds of the formula I, in which R 2 3 denotes a nitrile group and R R and Y have the abovementioned meaning, can be prepared by reaction of compounds of the formula I, in which R denotes a carboxamido group. For these reactions, suitable dehydrating reagents, such as e.g. trifluoroacetic anhydride in suitable inert solvents such as, e.g. dioxane are used, in the presence of a weak base such as pyridine or triethylamine at temperatures between 0°C and room temperature, preferably at room temperature.

The compounds of the formula III can be prepared by known processes by reaction of compounds of the formula IV 2

C'H-X

S(IV)

R

in wh R 2 and R 3 have the abovementioned meaning and X denotes a Leaving group such as e.g. bromine, chlorine or a tosylate or mesylate group, with piperazine in the case where n denotes 2 or homopiperazine in the case where n denates 3, in a suitable solvent such as e.g.

dimethylformamide at temperatures between o0 C.and the boiling temperature of the reaction mixture.

The compounds of the formula IV are obtained in analogy to known processes from the corresponding alcohols of the formula V RA CV) 11 in which R and R have the abovementioned meaning.

In the case where X denotes a halogen atam, for example chlorine, the alcohols of the formuLa r eacted with a chLorinating agent such as e.g. to chLoride without solvent or in an inert solvent such as e.g. toluene, at temperatures between room temperature and the boiling temperature of the solvent. The bromine derivatives of the formula IV can be obtained by reaction with phosphorus tribromide.

Th alcohols of the formula V can be prepared by reaction of Grignard compounds of the formula VI or VIa, in which X' denotes a chlorine or bromine atom, with aLdehydes of the formula VII or VIIa R2 MgX 3MgX CHO R 2

-CHO

13

R

VI) (VIa) (Vita) in analogy to known processes (Houben WeyL XIII/Za, 289, 302) or carried out by reduction of ketones of the formula

VIII

C=O

(VIII)

in which R2 and R3 have the abovementioned meaning, with reductants such as zinc or sodium borohydride in suitable solvents such as e.g. methahol or ethano at room temperature or the boiling temperature of the solvent, preferabl.y at room temperature.

The compounds of the formula VIII, in which R 2 denotes a phenyl nucleus which is unsubstituted or substituted by a difluoromethoxy group, and R3 denotes a difluoromethoxy group, canr be prepared from corresponding monohydroxy- or dihydroxybenzophenones by reaction with difLuorochLoromethane in a mixture of dioxane and sodium hydroxide satution at temperatures between room temperature and the boiling temperature of the mixture, prefer- X ably at 50* -70*C. (Lit.: DE 3,017,339). Tte i ii i 12 -t difluoromethyLthio derivatives of the formula VIII can be obtained analogously.

The compounds of the formuLa I in which Y denotes the group B can be prepared by reaction of the known indale derivatives of the formuLa IX 0 H

OIX)

At

H

with compounds of the formul~a X CH N CX) OCH.- CH 2 where R and R have the abovementioned meaning.

The reactions can be carried ov; in aqueous dioxane or inother suitable soLvents.in the presence of alkali, preferably sodium hydroxide soLution. The reaction temperature an be between room temperature and the boiling temperature of the mixture. It is preferably between 500 and 700C.

2 The r-ompounds of the formuLa X, in hich R and R have the abovementioned meaning, can be prepared by riactioi of compounds of the formula XI

~OH

CH -N (XI) which are known or which can be prepared by known processes n which R2 and R have the abovementioned meaning, with epichLorohydrin in a suitable solvent, such as e.g.

dimethyl sulphoxide in the presence of alkali, preferably sodium hydroxide solution, at temperatures between Ooc.to 500C. preferably' room temperature.

The compounds of tie general formula XI can be prepared by reaction of benztiydryLamines of the general formula XII NI

A

:i 9 99 4 94 4 9 9* 99 13 R2 R3 CH-NH2 in which R 2 and R 3 have the meaning indicated, with epichlorohydrin in a suitable solvent such as methanol, preferably at room temperature to the boiling temperature of the mixture, in particular at 70 0

C.

The compounds of the formula XII can be prepared by processes which are known per se or analogously to the processes described here or analogously to processes which are known per se (literature: Beilstein, Fourth 10 Supplement, 12, System Number 1734 and Najer at at., Bl.

1959, 352-355).

Necessary esterification, if appropriate, of the hydroxyl g'-oup in the 3-aminopropoxy side chain can be carried out analogously to methods known for the preoaration of arnaogous esters of 3-amino-2-hydroxypropoxyaryl compounds, if necess'ry using selective conditions if other reactive groups are present.

The starting materials used are known or can be prepared PJy processes which are known per se or analogously to the processes described here or analogously to processes which are known per se.

The compounds of the general formula I can be both bases and acids or amphoteric and can therefore be isolated from the reaction mixtures in the form of their salts or acid addition salts. As bases, they can be converted into salts by known processes using suitable inorganic or organic acids or as acids with bases, can form, salts.

Physiologically tolerable salts or acid addition salts are preferred. For this purpose, for example, sulphuric acid or hydrohalic acids, for example hydrochloric acid, are suitable as inorganic acids, and, for example, fumaric acid, maleic acid, citric acid and tartaric acid are suitable as organic acids. For preparation, the alcoholic solution of a suitable acid is added to the hot alcoholic solution of the base and the salt is obtained after addition of ether. Preferred salts alre the alkali metal, .1-.II

-I-LWL+

*i 9 0 0 a 9.

0: *9 99 so 9 a 4.

p 9, 9 14 alkaline earth metaL and ammonium salts of the compounds of the formula I which are obtained with the corresponding bases, in particuLar sodium hydroxide or potassium hydroxide.

The compounds of the formula I according to the invention exhibit a centre of chirality on carbon atom 2 of the propoxy side chain and can, depending on the substituents, possess further asymmetric carbon atoms and therefore exist as raceriates and diasterLamers. Diastereomers can be resolved into their racemic modifications in a known manner based on the physicochemircal differences of their components. Racemates can be resolved by known meth- 0ds, for example by recrystallizing in optically active solvents;, by microorganisms or reaction with an opticatly active acid or base which forms a salt with the racemic compound, resolution of the diastereomers by fractional crystaltization and releasing the enantiomers by suitjble agents. Particularly suitable optically active acids are, for example, the d and I forms of tartaric gci ditoluyLtartaric acid, malic acid, mandelic acid, camphorsulfonic acid or pyrrolidonecarboxylic acid. Suitable optically active bases are alpha-phenylethyamine, methylamine, ephedrine, brucine and quinine. Advantageously, the more active of the antipodes is isolated. According to the invention, however, it is also possible to obtain the pure enantiomers by asyiietric synthesis.

The following examples serve to illustrate the i nyvention.

Example 1 4-(3-(4-((4-Difluoromethoxyphenyl)phonyLmethyl)piperazin-1-y)-2-hydroxypropoxy)-H-indoe-2-carbonitre g of 4-(3-(4-((4-difluoromethoxyphenyL)phenylmethyl)piperazin-1-yL)-2-hydroxypropoxy)-1H-indoLe- 2 -carboxamide ar, dissolved in a mixture of 36 mL of dioxane and 1.7 g of pyridine and 1.6 mt of trifLuoroacetic anhydride in 10.5 ml of dioxane are added at 10 0 C. After standing for two hours at room temperature, the mixture is stirred into ice water. It is then extracted with methylene chloride, washed with water, and the organic I L 15 phase is dried aver sodium suLphate and concentrated.

T,'e residue is purified by column chromatography on siLic a geL e Luen t, ch Lo roif or m /met h ano L 40: 2) YieLd 1.1 g M. 99' -103'C.(Z) as the tr if Luoroacetate Example la 4-(3-(4-C(C4-D if LuoromethoxyphenyL )phenylmethyl )p iperazin-1-yL )-2-hydrjaxypropoxy)-lH-indoLe-2-carboni tri Le g of 4-C2,3-epoxypropoxy)-lH-indoLe-2-carbonitri Le and 3.7 g of (4-d if L~oromethoxyphenyl~phenyLmethyL )piperazine are dissolved in 50 mL of methanol and heated for 3 hours under refLux. The fn ixture is then concentrated to dryness in vacua and the res idue is i -iturated wi th hexane, fi Ltered of f wi th suct ion and puri fied by column chromatography on s i Lica geL (eLuent: chloroform! methanol 40:2).

Y ield: 1 .2 g M .p 930 Example 2 0 (4-D if luoromethoxyphenyL )phenyLmethyL )p iperaz in-1-yL )-2-hydroxypropoxy)-lH-indoLe-2-carboxamide 3.45 g of 4-(2,3-epoxypropcxy -H-indoLe-2-carbc~xamidle and 4.709g of (4-dif luorome thoxyphenyL )phenyLme'.hyL )p iperaz ine are dissolved at 400C in 75 mL of.

inethanol. rhe mixture is then concentrated to dryness in 'vacuo, the syrupy res idue is heated at 80 0 C. Ior 15 minutes and, after cool ing, the sol idi fied produc t is tr iturated w ith hexane and f i Ltered of f w ith suc t ion.

Cr14cle yieLd: 6.7 9 (81%) Af ter column chromatograph ic purif icat ioi Yield: 2.689g (32.5Z) 102-106 0

C.(Z)

I ExampLe 3 (Dif LuoromethoxyphenyL )phe.nyLmethyL )piperaz ine 4.9 g of potass ium carbonate and 17.5 g of anhydrous piperazine are added to 18.3 g of 4-difLuoromethoxY- 6enzhydryL chloride in 50 ml of dimethyLformamide and the mixture is stirred at room temperature for 12 hours.

L. of water is then added to the reaction mixture, the

A

O

:*I

16- Latter is extracted with chlorof.;,- and the chloroform phase is washed with 1 N hydrochloric acid. The aqueous phase is rendered alkaline and extracted using chloroform.

The org.anic phase is dried and evaporated. 19.5 g of 1- ((difluoromethoxyphenyl)phenylmethyl)piperazine are obtained as a pale yellow oil.

Example 4 4-Difluoromethoxybenzhydryl chloride g of 4-difLuoromethoxybenzhydrol are dissolved in 440 ml of chloroform, the mixture is cooled to OOC. and 17.5 ml of thionyl chloride in 220 ml of chloroform are added. The mixture is allowed to stand for 24 hours at room temperature ind excess thionyl chloride and chloroform are removed by distillation. 47 g of 4-diftioromthoxybenzhydryl chloride are obtained as a yellow oil.

Example 4-Difluoromethoxybenzhydrol g of 4-difluoromethoxybenzophenone are reduced using sodium borohydride in 400 ml of methanol at 40 0

C.

After an hour, the mixture is concentrated to dryness, 1.2 I of water is added to the contents of the flask and the mixture is extracted with chloroform. The organic phase is then dried and concentrated.

Yield: 55 g of 4-difluoromethoxybenzhydrol as a pale brown oil.

Example 6 4-Difluoromethoxybenzophenone 100 g of 4-hydroxybenzophenone and 200 g of sodium hydroxide are dissolved in a mixture of 1 L of water and 500 ml of dioxane. The mixture is heated to 70 0 C.and a vigorous stream of difluorochloromethane (Frigen 22) is introduced. After 2 hours, the mixture is cooled to room temperature and 1 L of water is added to the contents of the flask. The mixture is extracted three times using 1.2 I of chloroform each time, the chloroform phase is extracted by shaking with 1 N sodium hydroxide solution, washed with water and the organic phase is dried using potassium -AQ. carbonate. After stripping off the solvent and subsequent Aistillation under vacuum, 60 g of 4-difluoroi~iB 17methoxybenzoPhenone are obtained as a pal e yel Low o O 131- -135' C 1. 0 rb a r ExampLe 7 1-CD i ph eny Lme th y 23-epo xyp rop ox y) a zet id in e 37.5 g of diphenyLrnethyLazetidin-3-oL are dissolved at room temperature in a mixture of 250 mL of dimethyL suLphoxide and 150 mL of 5% strength sodium hydroxide soLuticon, 65 ml of epichLorohydrin are added and the mixture is allowed to stand for 3 days at room temperature. The reaction mixture is ext racted us ing 300 ml of methyLene chloride, an'd the organic phase is dried over sodium suLphate and evaporated. The crude product is distilled in vacuo.

YieLd: 29.0 g of 1-CD iphenyLmethyL)-3-(2,3-epoxypropoxy)azet idi.ne B.p.1740-1 6OC.0,2 mbar Example 8 4-(3-(1-DiphenyLmethyLazetidin-3-oxy)-2-hydroxypropoxy -H-i ndoLe-2-carboxam ide 8.89g of 4-hydroxy-1H-indoLe-2-carboxamide are dissolved in 250 ml of 0.8 percent strength, sodium hydroxide solution and a solution of 16.3 g of 1-(diphenyLmethyL)-3-C2,.3-epoxypropoxy)azetidine in 250 ml of dioxane is added. The mixture is allowed to stand for 4 hours at room temperature and then' 4armed to'60 0 C.for a further hours. The reaction mixture is then stirred into 1 1of ice water and extracted twice with 500 ml oT methyLene chloride each, time. The organic phase is dried using potassium carbonate and the solvent is removed by distiLLation 'in vacuo. The residue is triturated twice with 100 ml of dliisoprop)1I ether eac~h time and filtered off with suction-.

TiieLd: 7.1 g of 4- 1-D iphenyLme thy Laze tid in-3-oxy )-2-hydroxypropoxy) 1!H-indo'e-2-carboxamide m.p. 4186 0

C.

A14, 18 ExampLe 9 4-(3-(1-Diphenylmethyazetidin-3-oxy)-2-hydroxypropoxy)- IH-indoe-2-carbonitrile 10.0 g of 4-(3-(1-diphenyLmethylazetidin-3-oxy)- 2-hydroxypropoxy)-1H-indoLe-2-carboxamide Are dissolved in a mixture of 112 mL of dioxane and 10 g of pyridine and mL of trifluoroacetic anhydride in 10 mL of dioxane are added at 100C. After standing for two hours at room temperature, the mixture is stirred into ice water.

The mixture is extracted using methyLene chloride, washed first with dilute NaOH, then with water, and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography on silica gel (eluent: chloroform).

Yield: 9.3 g of 4-(3-(1-diphenylmethylazetidin-3oxy)-2-hydroxypropoxy)-1H-indoIe-2-carbonitrie 830 850 C.

Example Preparation of ampoules Ampoules which contain the constituents mentioned in the following can be prepa.red in a known manner. The active compound is dissolved in water and 1,2-propanedio and filled into glass ampoules under nitrogen.

4-(3-(4-((4-(2-methoxyethoxy)-phenyL)phenylmethy)-piperazin-1-yl)-2hydroxypropoxy)-1H-indoe-2-carbonitri e 2 mg 1,2-propanedio 0.8 mL distilled water to make up to 2.0 ml Example 11 Preparation of tablets and capsules Tablets and capsules which contain the constituents indicated below are prepared by known procedures. These are suitable in dosage amounts of one tablet or capsule in each case three times daily for the treatment of the previously mentioned diseases, in particular cardiac insufficiency.

g~ I t 19 4 Constituents Weight (mg) Tablet Capsule 4-(2-methoxyethoxy)phenyl)phenyl.methyl )piperazin-lyL)hydroxypropoxy)-1H-indae-2carbonitrile 30 tragacanth lactose 247.5 300 maize starch talc magnesium stearate r Example 12 Preparation of ampoules Ampoules which contain the constituents mentioned

CC

15 in the following can be prepared in a known manner. The t tCactive compound is dissolved in water and 1,2-propanedio and flilled into glass ampoules under nitrogen.

4-(3-(l-diphenylmethylazetidin-3oxy)-2-hydroxypropoxy)-1H-indole- 2-carbonitrie 2 mg 1,2-propanedio 0.8 ml distilled water to make up to 2.0 mL Example 13 Preparation of tablets and capsules Tablets and capsules which contain the constituents tt indicated below are prepared by known procedures. These are suitable in dosage amounts of one tablet or capsule in each case three times daily for the treatment of the previously mentioned diseases, in particular cardiac insufficiency.

constituents Weight (mg) Tablet Capsule 4-(3-(1-diphenyLmethyLazetidin- 3-oxy)-2-hydroxypropoxy)-H-indoe- 2-carbonitrile 30 tragacanti Lactose 247.5 300 maize starch talc magnesium stearate The compounds of the f ormuLa I according to the in'vent ion indicated in the foL Lowing tabLe, in which Y denA,,tes the group A (Examples 14-75) can be obtained analogousLy to the previous exampLes: 2 OCH 2 C H CH 2 N N CH 06 H CH 2 n H *V rac" denotes raceic. Unless indicated otherwise by R 4 *the 2-hydroxyL group of the propoxyamino side chain is present in unesterified form.

"denotes that no asymmetric carbon atom is pree Conf ig. Conf iQ Example R 1 cR 2 (2?J 0 14 CU -(--0CIF 2 '-OCIIF 2 rac 2 -2 CU O~-CIIF 2 If 2 S s 16 CN O~-CIfF 2 if 2 S R 17 oil '-9~-OCIIF 2 If 2 rac rac 18 OfCI 3 O-CI IF 2 11 2 rac rac 19 CU C I ICIF 2 11 3 rac rac C14 O.CIfF 2 4-fCIIF 2 3 rac 21 CN 3-ilyridinyl 4-OCIIF 2 2 rac rac 2 CN 4-Pyridinyl 4-OCHF 22 rac rac 23 C14 2-Tienyl 4-fJC~iF 22 rac rac 24 C11 3-Thienyl '1-OCIIF 22 rac rac C S 3 C 4* e a C 5 S 555 *Se S S. S t* S S 5 4 S S -C C SOS C S S S 4 C Conf ig., n 1) Conf ig.

M. P. 0

C

Example 26 27 28 CF 3 -~-SCF 3 ~oci 2 f2-1t OCIIF 2 If 3 OIIF rac rac i-ac rac rac ra c rac 93 95 (Z) El 29 CN OCHF 2 EN -~-OCH 2CF3 .31 CN -j-SCHF 2 32 (Ni SCHF 2 33 CN c 2C3 34 co 2 Et OC-- I~F 2 rac rac i-ac rac i-ac rac rac rac rac raec rac rae 91 93 a. at. 4 S 4 4 4 a. a a a a 4 4 a a a a a a.

a. a 4 4

S

ExampLe

R

3 !i C01H 2 Conf ig.

C A, Confi

T

Ck(2) 0

C

O- SCH-F 2 F 2CHO CN -9n ocli 2-c CH 2- O 3 4-SCHF 2 2- OCHF 2 11 r a c rac rac r ac 108 110 102 104.

7-, .4 .4*4 a 4* 0 .4 4 .4 .4 .4 44 .4 a 44.444 4,44.4 4. .4 -4 .4 .4 an Conf ig.

ExampLe Conf ig.

C(2) r a c M.P. C 89 91 38 CN Ok~-CH 2 -CH 2 -OC H -,CC -C 3 39 CN b--OCH 2 2 H2 OC CH3 CN -ACH2 -CH 2CHS 2 3 41 CU -CH -S-CM 412 2-11 3 0 0 42 CN -COf S-CH 3 0 43 C N 0C C CM H-CM -N, H 2 H- 2 i-ac r-a c r a c H 2 H 2 H 2 ra c r-ac.

rac r-a c ra c r a c 204 207 H 2 H 2 ra c 3 i-ac i-ac

F

a

C..

0CW 5* 4 a 0 4 4 6. 4 I C C C

*~C

C. C 4 C -t C a a C

C

I Conf ig.

C

(I

Config C A ExampLe

RI?

MI.P. C 4 5 CN O2--C2 15 46 CU C 1I 2 O-C 3 11 7 47 c l -O 2-o i 3 48 CUN 00--s-cii 2 2 fZ3O 0 0 CN -S -CI I O -DCII CU 1--sC 2 2 3 *1 cNc 1 2 -COf 2-0-C 2If If rac rac II 2 rac If 2 ra c rac If 2 rac ra c rac rac If 2 rac rac 11 2 rac 9 I~ At p .00 0*9 0 9* .6 t~ 5 .6 ~6 t~ S S t St C p S p 99 0 06.9 .6 .6 a a 9 99.

0*9 .S *5 9 9 .6 a 6 *9 9 9 9 a 9 6 9~.6 9 6 Conf ig.

n C* 1) Conf ig.

C A (2 M.P.

Example CN -l s-c II 2 3 i, 2 ra c CN II I 0 0 C N CI- s-Cl' 2 It 3 0 Oc 1I 2-COf 2-OCII 2 2- 3 Ii 2 ra c II2 II2 II2 rac r ac

S

S

r ac I"a c 86 87

I"

1 1 A

*GS

*0~ p 4 4* P

S

4. 4 6 4 604 P 64 6 4 4 p4.

A 4 4 'S 4 e S 4 p4* 4 Conf i g Cl CA (I Conf ig.

C.A(2) Exampte M.P. C CN j--ocii 2 Of2-oi 3 11 2 c C N 0 IIf OCI I F 2 61 c N OCCiIF2 oc-ocl2 of[2-O 2 -0 13 Ii2 ii 2 11 2 ra c Sa c rac ra c r a c r ac ra c 1- 4 da -i 4, a -e a a S a Conf i g.

n C AL Conf i g A( 2 M.P.

Example

R

c N Cl -0(O11ci 63 2 2to-OC 11 2- Ci 2-0(11l 77 78 64 CN j-c I 1 2 -Ol 3 4-Ciu 2 OCl 3 2 rac C-NW4, 0 -0011FI 2 66 67 68 'If 69 701 <4 Ctl 1-CHF 2 c N

OH

CII 12

H

H

IH

2 rae.

2 roe 2 ro roe raf, roeI rnc rac V.6-93 -1 G-I I 1 C -N 2

II

C)

YNOCHI-CII -OCH.

1 2 3 95-96) 113-123 CN Hl- 2 C -H" t ~29 F or the preparation of the compound of Example 27, 4-C2-methoxyethoxybenzophenone is obtained by reaction of 4-hydroxybenzophenone with 2-methoxyethyL chLoridle at 100'C..

in the presen-ce of sodium hydride in dimethyLf ormamide.

Furthe r react ion t a kes p Lace i n ac cordlanc e w ith Ex amp Le 1- 4-CZ.-Methaxyethoxy) -benzophenone is reduced to 4-(2methoxy-etJhoxy)benzhydroL using sodium borohydridle. 4-(2- Methoxyethoxy)benzhydroL is reacted with thionyl chloride in chLoroform to give 4-(2-methoxyethoxy)benzhydryL chLoride. 4-(2-methoxyethoxy)benzhydryL chloride is reacted with piperazine in dimethyLformamide in the presence of potassium carbonate to give 1-(C4-C2-methoxyethoxy)phenyL)phenyLmethyL)piperazine.

4-(2,3-Epoaxyp ropoxy)-lH-ir-doLe-2-carboxamide is reacted with 1-C (4-C2-methoxyethoixy)phenyL)phenyLmethyL)piperazime to give 4-(3-(4-((4-C2-methoxyethoxy)phenyL)phenyLme thy L )p iper az i n-1-yL )-2-hydroxypropoxy)-1H- i ndoLe- 2-carboxamide. The compound obtained is reacted with trifLuoroacetic anhydride in a mixture of dioxane and pyridine to give 4-C3-(4-((4-(2-methoxyethoxy)phenyL)phenyLmethyL)piperazin-1-yL)-2-hydroxypropoxy)-1H-ind.oLe- 2-carbonitriLe.

The esterified compounds of the formula Ia ca n be obtained by reaction of -corresponding compounds of the formula I with anhydrides of the formula R 4 COOCOR 4 or acid haLidesof the formula R 4COHaL, in p'articu.Lar R 4 CO0CL if appropriate in a solvent such as pyridine. T h compound of Example 71 can be prepared by reaction of th e compound of ExampLe 27 with acetic anhydride at room temperature.

"YN

w S S C S S. El S 5 S 5 5 9 S S *4 C 5~ S S *55 55. 0 *5 5 S S S S S S S S S S S S S 555 S S C S C S C S C S The following compounds of the formuLa Ia, in by esterification of compounds of.

1 the formula which Y denotes the group A, can be obtained Example RI 2 71 C N C1 01 72 CN 0 oclC11 OCII 2 2 3 73 CN -(jOCii 2 lfiioi -0: Config.

n C 1) 2rac 2 rac Config.

2) M. P. 0C I' a C r, a c 1/1 tj--o([1 (1 2 OC I3 C N &j-0CIIF 2 C11 Ci (Di r a) c rac 166-168 f

-A

31 The compounds of the formula I according to the invclntion, in which Y denotes the group B indicated in the following table, (Examples 76-85) can be obtained analogously to the previous Examples H2

N-OH

0 C -H CH- CH -oK O H H R a a~ a.

a a a.

a a a.

a a.

a a a *q a a a a.

a aa a a a a.

a ha a a aa*a a a~ a a a* a a a~ a a.

5 "rac" denotes racemic. Unless indicated otherwise by R4 the 2-hydroxyL group of the propoxyamino side chain is present in unesterified form.

denotes that no asymmetrical carbon atom is pres e nt.

4 o S .0 0 4 040 #40 0 Sow a 0* 0 0 0 0 *0 0 0 4 0 0 0 4 4 *4 S ego age 0 *4 ~s a e a a 4 4 a a a 4 0 a 4 4 0*0 4 fl ExampLe 16 71 78 79 81 a;, 83 8, L. 11 C N C N C N C N Co NI 12 C N C N C N P'liery I IPheny I 1.-C [-PhenyL Iheny L Pherty I I, It eny L.

4 f -1h.'riy I.

Ph eny L phenly I 3- OCI 13 2-cl 4-C L

I.-F

O-(CI 2OCII Conf ig.

rac rac rac rac Conf ig.

A

C)

I' a c ra c ratc r ac

M.P.

186 78 79 r, a c 6 6 66 *8 n* fl C d, fl A r~ 4 The fo~te aing compound of the formula Ia, in which Y denotes the group B, can be obtained by esterification of compounds of the formuLa I: ExampLe R 4 CH 3 Conf i g.

C (1) Conf ig.

A

C (2) M.P. C r a c rac 61 63

Claims (3)

1. Substituted indolylpropanols of the formula I .9' I 9 99 9 9 9 9 9 9 4 .44. 9 94 9 99R 9 in which, R 1 deiotes a cyano, carboxamido, alkoxycarbonyl, hydroxy'l or acetyl group, R 21denotes pyridinyl, thienyl, phenyl or substituted phenyl 'which is monosubstituted or disubstituted by halogen, alkyl, cycloalkyl, alkoxy, difluoromethoxy, 9 difluorornethylthio, trifluoromethoxy, trifluorornethylthio, trifluoroethoxy, alkoxyalkoxy, cycloalkylalkoxy, alkoxyalkyl, alkylthioalkoxy, alkylsuiphinylalkoxy, alkylsuiphonylalkoxy, alkoxyalkylthio,' alkoxyalkylsuiphinyl, alkoxyalkylstilphonyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsuiphonylalkyl and dialkylaminoalkoxy, and R3 3U denotes hydrogen, alkoxy, halogen, difluoromethoxy, difluorornethylthio, trifluoromethoxy, trifluoromethylthio, trifluoroethoxy, alkoxyalkoxy, alkoxyalkyl, alkylthioalkoxy, alkylsuiphinylalkoxy, alkylsulphonylalkoxy, 94 alkoxyalkylthio, alkoxyalkylsulphinyl, alkoxyalkylsuiphonyl, alkylthioalkyl, alkylsulphinyla.lkyl, 9 alkylsuiphonylalkyl or dialkylaminoalkoxy, or a physiologically tolerable hydrolysable derivative thereof in which the hydroxyl group in the 2-position of the 3-amiznopropoxy side chain is present in esterified form, and also their tautomeric forms and their physiologic(ally tolerable salts, where in all cases previously mentioned alkyl of the alkyl groups or of alkyl moieties or alkylene moieties of groups in each case LI A.4 denotes straight-chain or branched alkyl or alkylene 9 9 9 9' 9 0 i j i c rc~- ii 35 having 1 to 6 carbon atoms and cycloalkyl has 3 to 7 carbon atoms.

2. The compound according to claim 1 which is

4-(3-(l-Diphenylmethylazetidin-3-oxy)-2-hydroxypropoxy)-lH- indole-2-carbonitrile. 3. A compoeition suitable for the treatment of cardiac insufficienc cardiac arrhythmias, hypertonia, coronary heart diseases or peripheral or central arterial circulatory disturbances comprising an amount effective therefor of a compound or salt according to claim 1 and a pharmaceutically acceptable diluent. 4. A method of treating a ptient afflicted with cardiac insufficiency, cardiac arrhythmia, hypertonia, coronary heart disease or peripheral or central arterial circulatory disturbance comprising administering to such patient an amount effective therefor of a compound or salt according to claim 1. DATED this 14th day of SEPTEMBER, 1990. BEIERSDORF AKTIENGESELLSCHAFT Attorney: LEON K. ALLEN Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS i 74,